Von Willebrand disease (VWD) is a common and highly variable bleeding disorder with incomplete penetrance and variable expressivity. The ABO blood group is the only well-characterized human genetic modifier of Von Willebrand Factor (VWF) with a contribution of up to 30% of the genetic component. Patients with VWD show considerable variation in bleeding tendency even within the same family, independently of VWF levels. Therefore it is highly likely that modifier genes influence the phenotype. Lack of understanding of VWD modifier genes limits diagnosis and treatment. The overall goal of this proposal is to identify genetic loci that are modifiers of VWF levels and bleeding severity in humans. Through linkage mapping, using large pedigrees, we aim to discover genes that exert a modifier effect on VWF levels and bleeding severity. This study will be performed using extended pedigrees and small nuclear families collected through a multi- institutional effort. Aim 1 will focus on the collection of samples from large pedigrees with VWD and their phenotypic characterization. We have already collected and characterized a 758-member Amish pedigree from northern Indiana and a 24-member pedigree from Iowa diagnosed with VWD. We have identified and will recruit 8 additional pedigrees of at least 6 affected individuals each through a collaborative effort. Aim 2 will identify candidate genetic regions for VWF levels and bleeding in these large pedigrees with VWD. We will perform a genome wide scan on the Amish and Iowa pedigrees. We will also conduct genome scans in all additional pedigrees. Aim 3 will focus on the fine mapping of loci identified in the genome-wide scans and subsequent gene/mutation identification. The candidate regions will be narrowed using linkage disequilibrium testing in the extended set of unrelated families from Iowa and in families from Canada, Europe and the rest of the US that are available to us through a collaboration with Dr. Robert Montgomery. The regions will be examined for candidate genes that seem plausible on biological grounds for serving as modifiers of VWD. Candidate genes will be sequenced, and identified mutations will be confirmed by further sequencing and co segregation analysis. Overall we believe that this project will provide new insights into the genetics of VWD and could have important implications for understanding the genetic basis of bleeding and thrombosis.